Effects of di(2‐ethylhexyl)phthalate on testicular oxidant/antioxidant status in selenium‐deficient and selenium‐supplemented rats

Di(ethylhexyl)phthalate (DEHP), the most widely used plasticizer, was investigated to determine whether an oxidative stress process was one of the underlying mechanisms for its testicular toxicity potential. To evaluate the effects of selenium (Se), status on the toxicity of DEHP was further objective of this study, as Se is known to play a critical role in testis and in the modulation of intracellular redox equilibrium. Se deficiency was produced in 3‐weeks‐old Sprague–Dawley rats feeding them ≤0.05 mg Se /kg diet for 5 weeks, and Se‐supplementation group was on 1 mg Se/kg diet. DEHP‐treated groups received 1000 mg/kg dose by gavage during the last 10 days of the feeding period. Activities of antioxidant selenoenzymes [glutathione peroxidase 1 (GPx1), glutathione peroxidase 4 (GPx4), thioredoxin reductase (TrxR)], catalase (CAT), superoxide dismutase (SOD), and glutathione S‐transferase (GST); concentrations of reduced glutathione (GSH), oxidized glutathione (GSSG), and thus the GSH/GSSG redox ratio; and thiobarbituric acid reactive substance (TBARS) levels were measured. DEHP was found to induce oxidative stress in rat testis, as evidenced by significant decrease in GSH/GSSG redox ratio (>10‐fold) and marked increase in TBARS levels, and its effects were more pronounced in Se‐deficient rats with ～18.5‐fold decrease in GSH/GSSG redox ratio and a significant decrease in GPx4 activity, whereas Se supplementation was protective by providing substantial elevation of redox ratio and reducing the lipid peroxidation. These findings emphasized the critical role of Se as an effective redox regulator and the importance of Se status in protecting testicular tissue from the oxidant stressor activity of DEHP. © 2011 Wiley Periodicals, Inc. Environ Toxicol 29: 98–107, 2014.     

An association study of ABCG2 rs2231142 on the concentrations of allopurinol and its metabolites

ABCG2 is a gene that codes for the human breast cancer resistance protein (BCRP). It is established that rs2231142 G>T, a single nucleotide polymorphism of the ABCG2 gene, is associated with gout and poor response to allopurinol, a uric acid‐lowering agent used to treat this condition. It has also been suggested that oxypurinol, the primary active metabolite of allopurinol, is a substrate of the BCRP. We thus hypothesized that carrying the rs2231142 variant would be associated with decreased oxypurinol concentrations, which would explain the lower reduction in uric acid. We performed a cross‐sectional study to investigate the association between the ABCG2 rs2231142 variant and oxypurinol, allopurinol, and allopurinol riboside concentrations in 459 participants from the Montreal Heart Institute Hospital Cohort. Age, sex, weight, use of diuretics, and estimated glomerular filtration rate were all significantly associated with oxypurinol plasma concentration. No association was found between rs2231142 and oxypurinol, allopurinol and allopurinol riboside plasma concentrations. Rs2231142 was not significantly associated with daily allopurinol dose in the overall population, but an association was observed in men, with T carriers receiving higher doses. Our results do not support a major role of ABCG2 in the pharmacokinetics of allopurinol or its metabolites. The underlying mechanism of the association between rs2231142 and allopurinol efficacy requires further investigation.

Study Highlights

• WHAT IS THE CURRENT KNOWLEDGE ON THE TOPIC?

ABCG2 is a gene that codes for the human BCRP. It is established that rs2231142 G>T, a single nucleotide polymorphism of the ABCG2 gene, is associated with gout and poor response to allopurinol, a uric acid‐lowering agent used to treat this condition. It is not clear if pharmacokinetic changes are involved in the underlying mechanism of those observations.

• WHAT QUESTION DID THIS STUDY ADDRESS?

This study addressed whether the rs2231142 loss‐of‐function variant is associated with decreased oxypurinol concentrations.

• WHAT DOES THIS STUDY ADD TO OUR KNOWLEDGE?

Our results do not support a major role of ABCG2 in the pharmacokinetics of allopurinol or its metabolites.

• HOW MIGHT THIS CHANGE CLINICAL PHARMACOLOGY OR TRANSLATIONAL SCIENCE?

Further investigations of the links between ABCG2 rs2231142 and the pharmacodynamics of allopurinol are needed.     

Preliminary study on the role of the human IZUMO gene in oocyte-spermatozoa fusion failure

We studied the IZUMO gene 9 coding exons sequence in four groups of patients including those with fertilization failure by conventional IVF. We observed in our populations two combinations of four polymorphisms that appeared to be preferentially linked (CGG-CG and TAA-TT) without any significant difference between different genotype repartitions.     

Comparison between ultrasound and magnetic resonance imaging in assessment of fetal cytomegalovirus infection

OBJECTIVE: To evaluate whether fetal brain magnetic resonance imaging (MRI) adds useful information to the one obtained by ultrasound in fetuses with cytomegalovirus (CMV) infection. METHODS: MRI and ultrasonographic findings were analyzed retrospectively in 38 fetuses with proven congenital CMV infection. Both techniques were performed on the same week at a mean gestational age of 33 weeks (24-37). The referral indications were maternal seroconversion (n = 19), and ultrasound findings (n = 19). The results were compared with the fetopathologic examination in cases with fetal death or termination of pregnancy (TOP) or the infant's neurological examination. RESULTS: The 38 cases were classified into three groups, depending on ultrasound findings at referral. Group 1: no ultrasound features (n = 11); group 2: extracerebral features without cerebral abnormalities at ultrasound (n = 13); group 3: presence of cerebral features at ultrasound (n = 14). In group 1, MRI was always normal. In group 2, MRI revealed cerebral features in six cases (46%). In group 3, MRI always confirmed the lesions seen at ultrasound and highlighted other cerebral features. CONCLUSIONS: MRI can provide important additional information with regard to abnormal gyration, cerebellar hypoplasia, or abnormal signal in white matter. It is certainly useful in the assessment of fetuses with extracerebral features without brain abnormalities detected with ultrasounds. If the fetal ultrasound is strictly normal in an infected fetus, MRI may not detect brain anomalies; however, it seems difficult to not perform this noninvasive procedure.     

Hypophosphatasia: molecular testing of 19 prenatal cases and discussion about genetic counseling

OBJECTIVE: We studied hypophosphatasia (HP) mutations in 19 cases prenatally detected by ultrasonography without familial history of HP. We correlated the mutations with the reported ultrasound signs, and discussed genetic counseling with regard to the particular dominantly inherited prenatal benign form of HP. METHOD: The coding sequence of the tissue nonspecific alkaline phosphatase (TNSALP) gene was analyzed by DNA sequencing, and 3D modeling was used to locate the mutated amino acids with regard to the functional domains of TNSALP. RESULTS: Although reported ultrasound signs were heterogeneous, two mutated alleles were found in 18 of the 19 cases studied, indicating recessive transmission of the disease. Functional domains of TNSALP were affected by 74% of missense mutations. In all the cases, including one with only a heterozygous mutation, molecular, biological, and familial data do not corroborate the hypothesis of prenatal benign HP. The mutation c.1133A>T observed in the prenatal benign form of HP and common in USA was not found in this series. CONCLUSION: The results point out the prenatally detectable allelic heterogeneity of HP. The nature of the detected mutations and the evidence of recessive inheritance do not support these cases being affected with prenatal benign HP.     

The role of high-risk HPV-DNA testing in the male sexual partners of women with HPV-induced lesions

OBJECTIVES: The objectives were to assess the prevalence of high-risk HPV in the male sexual partners of women with HPV-induced lesions, and correlate it with biopsies guided by peniscopy. STUDY DESIGN: Fifty-four asymptomatic male sexual partners of women with low-grade squamous intra-epithelial lesions (LSIL) associated with high-risk HPV were examined between April 2003 and June 2005. The DNA-HPV was tested using a second-generation hybrid capture technique in scraped penile samples. Peniscopy identified acetowhite lesions leading to biopsy. RESULTS: High-risk HPV was present in 25.9% (14 out of 54) of the cases. Peniscopy led to 13 biopsies (24.07%), which resulted in two cases of condyloma, two cases of intra-epithelial neoplasia (PIN) I, one case of PIN II, and eight cases of normal tissue. The high-risk HPV test demonstrated 80% sensitivity, 100% specificity, 100% positive predictive value, and 88.9% negative predictive value for the identification of penile lesions. There was a greater chance of finding HPV lesions in the biopsy in the positive cases of high-risk HPV with abnormal peniscopy (p=0.007); OR=51 (CI 1.7-1527.1). CONCLUSION: Among asymptomatic male sexual partners of women with low-grade intra-epithelial squamous lesions, those infected by high-risk HPV have a higher chance of having abnormal penile tissue compared with male partners without that infection.